Novel compounds

ABSTRACT

The invention provides compounds of general formula (I) wherein m, n, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are as defined in the specification, process for their preparation, pharmaceutical compositions containing them and their use in therapy.

The present invention relates to novel compounds, processes for theirpreparation, pharmaceutical compositions containing them and their usein therapy.

Chemokines play an important role in immune and inflammatory responsesin various diseases and disorders, including asthma and allergicdiseases, as well as autoimmune pathologies. such as rheumatoidarthritis and atherosclerosis. These small secreted molecules are agrowing superfamily of 8-14 ka proteins characterised by a conservedfour cysteine motif. The chemokine superfamily can be divided into twomain groups exhibiting characteristic structural motifs, the Cys-X-Cys(C-X-C) and Cys-Cys.(C-C) families. These are distinguished on the basisof a single amino acid insertion between the NH-proximal pair ofcysteine residues and sequence similarity.

The C-X-C chemokines include several potent chemoattractants andactivators of neutrophils such as interleukin-8 (IL-8) andneutrophil-activating peptide 2 (NAP-2).

The C-C chemokines include potent chemoattractants of monocytes andlymphocytes but not neutrophils such as human monocyte chemotacticproteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation,Normal T Expressed and Secreted), eotaxin and the macrophageinflammatory proteins 1α and 1β (MIP-1α and MP-1β.

Studies have demonstrated that the actions of the chemokines aremediated by subfamilies of G protein-coupled receptors, among which arethe receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. Thesereceptors represent good targets for drug development since agents whichmodulate these receptors would be useful in the treatment of disordersand diseases such as those mentioned above.

In accordance with the present invention, there is therefore provided acompound of general formula

wherein:

-   -   m is 0, 1, 2 or 3;    -   each R¹ independently represents halogen, cyano, nitro,        carboxyl, hydroxyl, C₃-C₆ cycloakl, C₁-C₆ alkoxy, C₁-C₆        alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NR⁹R¹⁰,        C₃-C₆ cycloalkylano, C_(1pk -C) ₆ alkylthio, C₁-C₆ akylcarbonyl,        C₁-C₆ allcarbonylamio, sulphonamido (—SO₂NH₂), C₁-C₆        alkylsuiphonyl, —C(O)NR¹¹R, —NR¹³ C(O)—_(p)R¹⁴, phenyl, or C₁-C₆        alkyl optionally substituted by carboxyl or C₁-C₆        alkoxycarbonyl;    -   p is 0 or 1;    -   X represents an oxygen atom or a CH₂, OCH₂, CH₂O, CH₂NH, NH,        carbonyl or sulphonyl group and Y represents a nitrogen atom or        a CH or C(OH) group, provided that when X represents an oxygen        atom or a CH₂O, CH₂NH or NH group, then Y represents a CH group;    -   Z¹ represents a bond or a group (CH₂)_(q) where q is 1 or 2;    -   Z² represents a bond or a group CH₂, with the proviso that Z¹        and Z¹ do not both simultaneously represent a bond;    -   Q represents an oxygen or sulphur atom or a group CH₂ or NH;    -   R² represents a group    -   n is 0, 1 or 2;    -   each R³ independently represents a C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, —CH₂OH or carboxyl group;    -   R⁴, R⁵, R⁶ and R⁷ each independently represent a hydrogen atom        or a C₁-C₆ alkyl group, or R⁴, R⁵, R⁶ and R⁷ together represent        a C₁-C₄ alkylene chain linking the two carbon atoms to which        they are attached to form a 4 to 7-membered satrn carbocycle, or        R⁵, R⁶ and R⁷ each represent a hydrogen atom and R⁴ and R⁸        together with the carbon atoms to which they are attached form a        5- to 6-membered saturated carbocycle;    -   R⁸represents a hydrogen atom, a C₁-C₆ alkyl group or is linked        to R⁴ as defined above;    -   R⁹ and R¹⁰ each independently represent a hydrogen atom or a        C₁-C₆ alkyl group, or R⁹ and R¹⁰ together with the nitrogen atom        to which they are attached form a 4 to 7-membered saturated        heterocycle;    -   R¹¹ and R¹² each independently represent a hydrogen atom or a        C₁-C₆ alkyl group optionally substituted by C₁-C₆        alkoxycarbonyl;    -   R¹³represents a hydrogen atom or a C₁-C₆ alkyl group;    -   R¹⁴ represents a hydrogen atom, or a C₁-C₆ alkyl group        optionally substituted by carboxyl, C₁-C₆ alkoxy or C₁-C₆        alkoxycarbonyl;    -   R¹⁵ represents a group C₂-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆        cycloalkyl, C₅-C₆ cycloalkenyl, adamantyl, phenyl or a saturated        or unsaturated 5- to 10-membered heterocyclic ring system        comprising at least one heteroatom selected from nitrogen,        oxygen and sulphur, wherein each group may be optionally        substituted by one or more substituents independently selected        from nitro, hydroxyl, oxo, halogen, carboxyl, C₁-C₆ alkyl, C₁-C₆        alkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl, C₁-C₆        alkoxycarbonyl, phenyl and —NHC(O)—R¹⁷ with the proviso that R¹⁵        does not represent an unsubstituted 1-pyrrolidinyl, an        unsubstituted 1-piperidinyl or an unsubstituted        1-hexamethyleneiminyl (1-homopiperidinyl) group;    -   t is 0, 1, 2 or 3;    -   each R¹⁶ independently represents halogen, cyano, nitro,        carboxyl, hydroxyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆        alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NR¹⁸R¹⁹,        C₃-C₆ cycloalkylammo, C₁-C₆allylthio, C₁-C₆ alkylcarbonyl, C₁-C₆        alkylcarbonylamino, sulphonamido (—SO₂NH₂), C₁-C₆ alkylsuphonyl,        —C(O)NR²⁰R²¹, —NR²²C(O)(NH)_(v)R²³, phenyl, or C₁-C₆ alkyl        optionally substituted by carboxyl or C₁-C₆ alkoxycarbonyl;    -   R¹⁷ represents a C₁-C₆ alkyl, amino (—NH₂) or phenyl group;    -   R¹⁸ and R¹⁹ each independently represent a hydrogen atom or a        C₁-C₆ alkyl group, or R¹⁸ and R¹⁹ together with the nitrogen        atom to which they are attached form a 4- to 7-membered        saturated heterocycle;    -   R²⁰ and R²¹ each independently represent a hydrogen atom or a        C₁-C₆ alkyl group optionally substituted by C₁-C₆        alkoxycarbonyl;    -   v is 0 or 1;    -   R²² represents a hydrogen atom or a C₁-C₆ alkyl group; and    -   R²³ represents a hydrogen atom, or a C₁-C₆ alkyl group        optionally substituted by carboxyl, C₁-C₆ alkoxy or C₁-C₆        alkoxycarbonyl;        or a pharmaceutically acceptable salt or solvate thereof.

In the context of the present specification, an alkyl or alkenylsubstituent group or an alkyl or alkenyl moiety in a substituent groupmay be linear or branched. In the definition of R¹⁵, it should be notedthat the unsaturated 5- to 10-membered heterocyclic ring system may bealiphatic or aromatic.

The integer m is preferably 1 or 2.

Each R¹ independently represents halogen (e.g. chlorine, fluorine,bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C₃-C₆ cycloalkyl(cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl), C₁-C₆, preferablyC₁-C₄, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C₁-C₆,preferably C₁-C₄, alkoxycarbonyl (e.g. methoxycarbonyl orethoxycarbonyl), C₁-C₆, preferably C₁-C₄, haloalkyl (e.g.trifluoromethyl), C₁-C₆, preferably C₁-C₄, haloalkoxy (e.g.trifluoromethoxy), —NR⁹R¹⁰, C₃-C₆ cycloalkylamino (e.g.cyclopropylarnio, cyclobutylamino, cyclopentylamino or cyclohexylamino),C₁-C₆, preferably C₁-C₄, alkylthio (e.g. methylthio or ethylthio),C₁-C₆, preferably C₁-C₄, alkylcarbonyl (e.g. methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,n-pentylcarbonyl or n-hexylcarbonyl), C₁-C₆, preferably C₁-C₄,alkylcarbonylanino (e.g. methylcarbonylamino or ethylcarbonylamino),sulphonauido, C₁-C₆, preferably C₁-C₄, alkylsulphonyl (e.g.methylsulphonyl ethylsulphonyl, n-propylsulphonyl isopropylsulphonyl,n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), —C(O)NR¹¹R¹²,—NR¹³C(O)—(NH)_(p)R¹⁴, phenyl or C₁-C₆, preferably C₁-C₄, alkyl (e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl isobutyl, tert-butyl,n-pentyl or n-hexyl) optionally substituted by carboxyl or C₁-C₆,preferably C₁-C₄, alkoxycarbonyl (e.g. methoxycarbonyl orethoxycarbonyl).

Most preferably, each R¹ independently represents halogen (particularlychlorine or fluorine), cyano, nitro, C₁-C₆ alkoxy (especially methoxy),C₁-C₆ alkylcarbonyl (especially methylcarbonyl) or C₁-C₆alkylcarbonylamino (particularly methylcarbonylamino). Each R¹especially represents halogen or cyano

Preferably X represents an oxygen atom or a CH₂ or NH group.

Preferred combinations of Y, Z¹ and Z² include: Y Z¹ Z² CH CH₂ bond CHbond CH₂ CH CH₂ CH₂ CH (CH₂)₂ bond N CH₂ CH₂

Q preferably represents an oxygen atom.

Each R³ independently represents a C₁-C₆, preferably C₁-C₄, alkyl (e.g.methyl, ethyl n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hecyl), C₁-C₆, preferably C₁-C₄, alkoxycarbonyl (e.g.methoxycarbonyl or ethoxycarbonyl), —CH₂OH or carboxyl group. It ispreferred that R³ represents a methyl, methoxycarbonyl, ethoxycarbonyl—CH₂OH or carboxyl group.

R⁴, R⁵, R⁶ and R⁷ each independently represent a hydrogen atom or aC₁-C₆, preferably C₁-C₄, alkyl (e.g. methyl ethyl, n-propyl, isopropyl,n-butyl, isobutyl tert-butyl, n-pentyl or n-hexyl), or R⁴, R⁵, R⁶ and R⁷together represent a C₁-C₄ alkylene chain linking the two carbon atomsto which they are attached to form a 4 to 7-membered saturatedcarbocycle (e.g. cyclohexyl or preferably cyclopentyl), or R⁵, R⁶ and R⁷each represent a hydrogen atom and R⁴ and R⁸ together with the carbonatoms to which they are attached form a 5- to 6-membered saturatedcarbocycle (preferably cyclopentyl).

R⁸ represents a hydrogen atom, a C₁-C₆, preferably C₁-C₄, alkyl group(e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl) or is linked to R⁴ as defined above.

R⁹ and R¹⁰ each independently represent a hydrogen atom or a C₁-C₆,preferably C₁-C₄, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, teit-butyl, n-pentyl or n-hexyl), or R⁹ and R¹⁰together with the nitrogen atom towhich they are attached form a 4- to7-membered saturated heterocycle.

R¹¹ and R¹² each independently represent a hydrogen atom or a C₁-C₆,preferably C₁-C₄, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionallysubstituted by a C₁-C₆, preferably C₁-C₄, alkoxycarbonyl substituentgroup.

R¹³ represents a hydrogen atom or a C₁-C₆, preferably C₁-C₄, alkyl group(e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl).

R¹⁴ represents a hydrogen atom, or a C₁-C₆, preferably C₁-C₄, alkylgroup (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxylC₁-C₆, preferably C₁-C₄, alkoxy or C₁-C₆, preferably C₁-C₄,alkoxycarbonyl.

R¹⁵ represents a group C₂-C₆, preferably C₂-C₄, alyl group (e.g. ethyln-propyl, isopropyl, n-butyl, isobutyl tert-butyl or n-pentyl), C₂-C₆,preferably C₂-C₄, alkenyl C₃-C₆ cycloalkyl (e.g. cyclobutyl orcyclopentyl), C₅-C₆ cycloalkenyl, amntyl, phenyl or a saturated orunsaturated 5- to 10-membered heterocyclic ring system comprising atleast one heteroatom selected. from nitrogen, oxygen and sulphur,wherein each group may be optionally substituted by one or more (e.g.one, two, three or four) substituents independently selected from nitro,hydroxyl, oxo, halogen (e.g: fluorine, chlorine, bromine or iodine),carboxyl, C₁-C₆, preferably C₁-C₄, alkyl (e.g. methyl ethyl, n-propyl,isopropyl, n-butyl isobutyl, tert-butyl, n-pentyl or n-hexyl), C₁-C₆,preferably C₁-C₄, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy),C₁-C₆, preferably C₁-C₄, alkylthio (e.g. methylthio or ethylthio),C₁-C₆, preferably C₁-C₄, alkylcarbonyl (e.g. methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,n-pentylcarbonyl or n-hexylcarbonyl), C₁-C₆, preferably C₁-C₄,alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), phenyl and—NHC(O)—R¹⁷.

The saturated or unsaturated 5- to 10-membered heterocyclic ring systemmay be monocyclic or polycyclic (e.g. bicyclic) and may comprise up tofour heteroatoms independently selected from nitrogen, oxygen andsulphur. Examples of ring systems that may be used include pyrrolidinyl,piperidinyl, pyrazolyl, thiazolidinyl, thienyl, isoxazolyl thiadiazolyl,pyrrolyl, furanyl, thiazolyl, indolyl, quinolinyl, benzimidazolyl,triazolyl, tetraaolyl and pyridinyl.

Each R¹⁶ independently represents halogen (e.g. chlorine, fluorine,bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C₃-C₆ cycloalkyl(cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C₁-C₆, preferablyC₁-C₄, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C₁-C₆,preferably C₁-C₄, alkoxycarbonyl (e.g. methoxycarbonyl orethoxycarbonyl), C₁-C₆, preferably C₁-C₄, haloalkyl (e.g.trifluoromethyl), C₁-C₆, preferably C₁-C₄, haloalkoxy(e.g.trifluoromethoxy), —NR¹⁸R¹⁹, C₃-C₆ cycloalylamino (e.g.cyclopropylamino, cyclobutylamino., cyclopentylamino or cyclohexylamno),C₁-C₆, preferably C₁-C₄, alkylthio (e.g. methylthio orethylthio), C₁-C₆,preferably C₁-C₄, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyln-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonylor n-hexylcarbonyl), C₁-C₆, preferably C₁-C₄, alkylcarbonylamino (e.g.methylcarbonylamino or ethylcarbonylamino), sulphonamido, C₁-C₆,preferably C₁-C₄, alkylsulphonyl (e.g. methylsulphonyl, ethylsulphonyl,n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl,n-pentylsulphonyl or n-hexylsulphonyl), —C(O)NR²¹R²²,—NR²³C(O)—(NM)_(v)R²⁴, phenyl, or C₁-C₆, preferably C₁-C₄, alkyl (e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl isobutyl, tert-butyln-pentyl or n-hexyl) optionally substituted by carboxyl or C₁-C₆,preferably C₁-C₄, alkoxycarbonyl (e.g. methoxycarbonyl orethoxycarbonyl).

Preferably, each R¹⁶ independently represents halogen (particularlychlorine or fluorine), cyano, C₁-C₄ alkoxy (especially methoxy), C₁-C₄alkoxycarbonyl (especially methoxycarbonyl), C₁-C₄ haloalkyl (especiallytrifluoromethyl), C₁-C₄ akylcarbonyl (particularly methylcarbonyl),phenyl or C₁-C₄ alkyl (e.g. methyl or tert-butyl). Each R¹⁶ isespecially a halogen atom or methyl group.

R¹⁷ represents a C₁-C₆, preferably C₁-C₄, all group (e.g. methyl, ethyln-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl orn-hexyl), amino or phenyl group.

R¹⁸ and R¹⁹ each independently represent a hydrogen atom or a C₁-C₆,preferably C₁-C₄, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyln-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R¹⁹ and R²⁰together with the nitrogen atom to which they are attached form a 4 to7-membered saturated heterocycle. R²⁰ and R²¹ each independentlyrepresent a hydrogen atom or a C₁-C₆, preferably C₁-C₄, alkyl group(e.g. methyl ethyl, n-propyl, isopropyl, n-butyl isobutyl tert-butyln-pentyl or n-hexyl) optionally substituted by a C₁-C₆, preferablyC₁-C₄, alkoxyCarbonyl substituent group.

-   -   R²² represents a hydrogen atom or a C₁-C₆, preferably C₁-C₄,        alkyl group (e.g. methyl ethyl, n-propyl, isopropyl, n-butyl,        isobutyl, tert-butyl, n-pentyl or n-hexyl).

R²³ represents a hydrogen atom, or a C₁-C₆, preferably C₁-C₄, alkylgroup (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl,C₁-C₆, preferably C₁-C₄, alkoxy or C₁-C₆, preferably C₁-C₄,alkoxycarbonyl.

Preferred compounds of the invention include:

-   N-(5-Chloro-2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy})-phenyl)-isobutramide,-   Thiophene-2-carboxylic acid    (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   N-[(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)methyl]-benzamide,-   Pyrazine-2-carboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   Cyclohexanecarboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-phthalamic    acid methyl ester,-   N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydrpxy-butyramide,-   N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-ureido-acetamide,-   4-Acetylamino-N-(2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-butyramide,-   1-Acetyl-piperidine-4-carboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methoxy-benzamide,-   2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,-   2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,-   Adamantane-1-carboxylic acid    (2-{3-[34-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-phenyl-propionamide,-   N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-benzamide,-   5-Methyl-thiophene-2-carboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   1-Acetyl-pyrrolidine-2-carboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   1,5-Dimethyl-1H-pyrazole-3-carboxylic acid    (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   5-Oxo-pyrrolidine-2-carboxylic acid    (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   1H-Indole-6-carboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   Cyclobutanecarboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,-   Pentanoic acid    (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   Pent-4-enoic acid    (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   Cyclopentanecarboxylic acid    (2-{3-[3(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   Cyclopropanecarboxylic acid    (2-{3-[3-(chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isobutyramide,-   N2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methylsulfinyl-acetamide,-   2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,-   N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-butyramide,-   N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,-   N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-acetamide,-   N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2,2-dimethyl-propionamide,-   5-Oxo-hexanoic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   Hexanoic acid    (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   2-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,-   3-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,-   (4R)-N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-1,3-thiazlidine-carboxamide    ditrifluoroacetate,-   Thiophene-2-carboxylic acid    (2-{3-[4-(3,4dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,-   N-(2-{3-[4(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-nicotinamide,-   Pyridine-2-carboxylic acid    (2-{3-[4-(3,4dichloro-phenoxypiperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isonicotinamide,-   Cyclohexanecarboxylic acid    (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,-   5-Methyl-thiophene-2-carboxylic acid    (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   Cyclobutanecarboxylic acid    (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,-   Pentanoic acid    (2-{3-[4-(3,4dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   Pentenoic acid    (2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   Cyclopentanecarboxylic acid (2-{3-[4-(3    ,4dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,-   N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,-   N2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-2,2,2-trifluoroacetamide    hydrochloride,-   4-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)3-methyl-butyric    acid,-   N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-succinamic    acid,-   Furan-2-carboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   1H-Pyrrole-2-carboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   Thiophene-2-carboxylic acid    (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   Cyclopentanecarboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   5-Methyl-thiophene-2-carboxylic acid    (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4methyl-phenyl)-amide,-   3-Chloro-thiophene-2-carboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   5-Methyl-isoxazole-4-carboxylic acid    (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   [1,2,3]Thiadiazole-4-carboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidn-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   3-Methyl-furan-2-carboxylic acid    (2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   Cyclopent-1-enecarboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   2-Methyl-furan-3-carboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-methyl-phenyl)-amide,-   3-Methyl-thiophene-2-carboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   5-Nitro-1H-pyrazole-3-carboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}4-methyl-phenyl)-amide,-   Thiophene-3-carboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   Cyclobutanecarboxylic acid    (2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   Furan-2-carboxylic acid    (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   1H-Pyrrole-2-carboxylic acid    (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   Thiophene-2-carboxylic acid    (2-{3-[3-(4fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   3-Chloro-thiophene-2-carboxylic acid    (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   5-Methyl-isoxazole-4-carboxylic acid    (2-{3-[3-(4-fuoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   3-Methyl-furan-2-carboxylic acid    (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   Cyclopent-1-enecarboxylic acid    (2-{3-[3-(4fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   2-Methyl-furan-3-carboxylic acid    (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   3-Methyl-thiophene-2-carboxylic acid    (2-{3-[3-(4fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   5-Chloro-thiophene-2-carboxylic acid    (2-{3-[3-(4fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   Thiophene-3-carboxylic acid    (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   2,5-Dimethyl-furan-3-carboxylic acid    (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   Cyclobutanecarboxylic acid    (2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   Furan-3-carboxylic acid    (2-{3-[3-(4fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide,-   N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-1H-pyrrole-2-carboxamide,-   N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-3-thiophenecarboxamide,-   N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxy]phenyl}-2-thiophenecarboxamide,    compound with trifluoroacetic acid,-   N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-2-thiophenecarboxamide,-   N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]phenyl}-2-furancarboxamide,-   N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]phenyl}-1-pyrrole-2-carboxamide,-   N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-1H-pyrrole-3-carboxamide,-   N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-2-furancarboxamide,-   N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxy]phenyl}cyclopentanecarboxamide,    compound with trifluoracetic acid,-   N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,-   N-(2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,-   N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,-   N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,    and-   N-(2-{3-[4-(3,4-Dichloro-phenylamino)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide.

The present invention further provides a process for the preparation ofa compound of formula (I) as defined above which comprises reacting acompound of general formula

or a salt thereof (e.g. an acid addition salt such as a hydrochloridesalt), wherein m, n, t, R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁶, Q, Z¹ and Z²are as defined in formula (I), with a compound of general formulaR¹⁵—CO₂H  (III)or chemically equivalent derivative thereof (e.g. acyl halide oranhydride derivative) wherein R¹⁵ is as defined in formula (I);

-   -   and optionally thereafter forming a pharmaceutically acceptable        salt or solvate of the compound of formula (I) obtained.

The process of the invention may conveniently be carried out in asolvent, e.g. an organic solvent such as an alcohol (e.g. methanol orethanol), a hydrocarbon (e.g. toluene), an amine (e.g. triethylamine ordiisopropylethylamine) or acetonitrile at a temperature ot, for example,15° C. or above, such as a temperature in the range from 20 to 120° C.

Compounds of formulae (II) and (III) are either commercially available,are well known in the literature or may be prepared easily using knowntechniques.

It will be appreciated by those skilled in the art that in the processof the present invention certain functional groups such as hydroxyl oramino groups in the staring reagents or intermediate compounds may needto be protected by protecting groups. Thus, the preparation of thecompounds of formula (I) may involve, at an appropriate stage, theremoval of one or more protecting groups.

The protection and deprotection of functional groups is descnbed in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).

The compounds of formula (I) above may be converted to apharmaceutically acceptable salt or solvate thereof, preferably an acidaddition salt such as a hydrochloride, hydrobromide, phosphate, acetate,fumarate, maleate, tartrate, citrate, oxalate, methanesulphonateorptolienesulphonate.

Compounds of formula (I) are capable of existing in stereoisomericforms. It will be understood that the invention encompasses the use ofall geometric and optical isomers of the compounds of formula (I) andmixtures thereof including racemates. The use of tautomers and mixturesthereof also form an aspect of the present invention.

The compounds of formula (I) have activity as pharmaceuticals, inparticular as modulators of chemokine receptor (especially MIP-1αchemokine receptor) activity, and may be used in the treatment ofautoimmune, inflammatory, proliferative and hyperproliferative diseasesand immunologically-mediated diseases including rejection of taplantedorgans or tissues and Acquired Ilununodeficiency Syndrome (AIDS).

Examples of these conditions are:

-   -   (1) (the respiratory tract) airways diseases including chronic        obstructive pulmonary disease (COPD) such as irreversible COPD;        asthma, such as bronchial, allergic, intrinsic, extrinsic and        dust asthma, particularly chronic or inveterate asthmn (e.g.        late asthma and airways hyper-responsiveness); bronchitis;        acute, allergic, atrophic rhinitis and chronic rhinitis        including rhinitis caseosa, hypertrophic rhinitis, iinitis        purulenta, rhinitis sicca and rhinitis medicamentosa; membranous        rhinitis including croupous, fibrinous and pseudomembranous        rhinitis and scrofoulous rhinitis; seasonal rhinitis including        rhinitis nervosa (hay fever) and vasomotor rhinitis;        sarcoidosis, farmer's lung and related diseases, fibroid lung        and idiopathic interstitial pneumonia;    -   (2) (bone and joints) rheumatoid arthritis, seronegative        spondyloarthropathies (including ankylosing spondylitis,        psoriatic arthritis and Reiter's disease), Behcet's disease,        Sjogren's syndrome and systemic sclerosis;    -   (3) (skin) psoriasis, atopical dermatitis, contact dermatitis        and other eczmatous dermitides, seborrhoetic dermatitis, Lichen        planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa,        urticaria, angiodermas, vasculitides, eiydiemas, cutaneous        eosinophilias, uveitis, Alopecia areata and vernal        conjunctivitis;    -   (4) (gastrointestinal tract) Coeliac disease, proctitis,        eosinopilic gastro-enteritis, mastocytosis, Crohn's disease,        ulcerative colitis, food-related allergies which have effects        remote from the gut, e.g., migraine, rhinitis and eczema;    -   (5) (other tissues and systemic disease) multiple sclerosis,        atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS),        lupus erythematosus, systemic lupus, erythematosus, Hashimoto's        thyroiditis, myasthenia gravis, type I diabetes, nephrotic        syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous        leprosy, sezary syndrome and idiopathic thrombocytopenia pupura;    -   (6) (allograft rejection) acute and chronic following, for        example, tnsplantation of kidney, heart, liver, lung, bone        marrow, skin and cornea; and chronic graft versus host disease;    -   (7) cancers, especially non-sraill cell lung cancer (NSCLC) and        squamous sarcoma;    -   (8) diseases in which angiogenesis is associated with raised        chemokine levels (e.g. NSCLC); and    -   (9) cystic fibrosis, stroke, re-perfusion injury in the heart,        brain, peripheral limbs and sepsis.

Thus, the present invention provides a compound of formula (I), or apharmaceutically-acceptable salt or solvate thereof, as hereinbeforedefined for use in therapy.

In a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof as hereinbefore defined in the manufacture of amedicament for use in therapy.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention also provides a method of treating an inflammatory diseasein a patient suffering from, or at risk of, said disease, whichcomprises administering to the patient a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined.

The invention still further provides a method of treating an airwaysdisease in a patient suffering from, or at risk of, said disease, whichcomprises administering to the patient a therapeuticallyeffective amountof a compound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary s with the compound employed, the mode ofadministration, the treatment desired and the disorder indicated. Thedaily dosage of the compound of formula (I) may be in the range from0.001 mg/kg to 30 mg/kg.

The compounds of formula (I) and pharmaceutically acceptable salts andsolvates thereof may be used on their own but will generally beadministered in the form of a pharmaceutical composition in which theformula (I) compound/salt/solvate (active ingredient) is in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (per cent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined,,with a pharmaceuticallyacceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. tothe lung and/or airways or to the skin) in the form of solutions,suspensions, heptafluoroalkane aerosols and dry powder formulations; orsystemically, e.g. by oral administration in the form of tablets,capsules, syrups, powders or granules, or by parenteral administrationin the form of solutions or suspensions, or by subcutaneous ad i:stionor by rectal administration in the form of suppositories ortransdermally.

The invention will now be further explained by reference to thefollowing illustrative examples, in which ¹H NMR spectra were recordedon Varian Unity Inova 400. The central solvent peak of chloroform-d(δ_(H) 7.27 ppm) were used as internal standard Low resolution massspectra and accurate mass determination were recorded on aHewlett-Packard 1100 LC-MS system equipped with APCI/ESI ionisationchambers. All solvents and commercial reagents were laboratory grade andused as received. The nomenclature used for the compounds was generatedwith ACDUAC Name Pro. The following abbreviations are used in theexamples:

NMP: 1-Methyl-2-pyrrolidinone

DIMA: N,N-Diisopropylethylanine

HBTU: 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

HoBT: 1-Hydroxybenzotriazole

THF: Tetrahydrofuran

EXAMPLE 1N-(5-Chloro-2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isobutyramide

a) N-(5-Chloro-2-hydroxy-phenyl)-isobutyramide

In a flask was added 4-chloro-2-aminophenol (1.2 g, 8.39 mmole) andwater (25 ml). The suspension was vigorously stirred and isobutyricanhydride (1.6 ml, 10.5 inmole) was added. The mixture was heated to 60°C. for 30 minutes under vigorous stirring. The emulsion was cooled, anda precipitate was formed, which was collected through filtration. Thesolid was washed twice with water on the filter and was finally dried togive 1.4 g (78%) of the sub-title compound as a white solid.

¹H-NMR (400 MHz DMSO-d₆) δ: 10.11 (1H, s); 9.12 (1H, s); 7.94 (1H, d,J2.5 Hz); 6.95 (1H, dd, J 8.7 2.6 Hz); 6.84 (1H, d, J8.5 Hz); 2.79 (1H,p, J6.7 Hz); 1.08 (6H, d, J6.8 Hz)

b) N-(5-Chloro-2-oxiranylmethoxy-phenyl)-isobutyramide

In a vial was added the compound obtained in a) (0.4 g, 1.87 mmole),epibromohydrin (0.28 g, 2.06 mmole), K₂CO₃ (0.5 g, 3.7 mnmole) and DMF(2 ml). The vial was sealed and heated with stirrng (2 hours, 60° C.).The mixture was then partitioned between EtOAc and water, and theorganic phase was washed twice with water and once with brine, and wasfinally evaporated to give a brown solid. The crude epoxide was purifiedon silica, to give 0.22 g (44%) of the sub-title compound as a whitesolid.

c) In a vial was added the compound obtained in b) (0.026 g, 0.13mmole), 3-(4-chlorophenoxy)-pyrrolidine (0.035 g, 0.13 mmole) in ethanol(2 ml). The vial was sealed and heated with stirring at 75° C. for 3hours. The solution was allowed to cool, and the solvent was evaporated.The crude product was purified on silica, and the pure fractions werecollected. The title compound was lyophilized as the hydrochloride,giving 0.055 g (84%) as a white solid. The compound was a mixture offour stereoisomers, which had an effect on the NMR-spectra.

¹H-NMR (400 MHz, DMSO-d₆) δ: 10.84-10.34 (1H, m); 9.12 (1H, s); 8.09(1H, s); 7.36 (2H, dd, J 9.2 1.3 Hz); 7.11-7.00 (3H, m); 7.00 (211 d, J8.8 Hz); 6.22-6.06 (1H, m); 5.22-5.10 (1H, m); 4.34 (1H, bs); 4.08-3.96(1.5H, m); 3.95-3.87 (1H, m); 3.83-3.66 (1.5H m); 3.61-3.23 (3H, m);2.86 (1H, sept, J6.6 Hz); 2.64-2.51 (½H, m); 2.36-2.14 (1H, m);2.14-2.00 (½H, m); 1.08 (6H, d, J 6.7 Hz) APCI-MS: m/z 467.2 [MH+]

Aniline Intermediate 1

1-(2-aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-propanoldihydrochloride

N-(2-{3-[4-(3,4-chlorophenoxy)-1-piperidinyl]-2-hydroxypropoxy}phenyl)-acetamide(1.418 g, 3.13 mmol, prepared by analogy to Example 1) was dissolved in50 ml HCl (35%/aq, puriss) and refluxed overnight. The productprecipitated and was filtered and dried to give 0.835 g (65%) of thetitle compound.

APCI-MS m/z: 411, 413 [MH⁺]¹H NMR (400 Mz, CDCl₃): δ 8.39-3.31 (m, 2H),7.31(d, 1H), 7.01-6.98(m, 3E), 6.94-6.91(m, 1H), 6.75(dd, 1H), 4.31(m,1), 4.12-4.02 (m, 2H), 3.92(dd, 1H), 2.90(m, 1H), 2.69(m, 1H),2.62-2.51(m, 2H), 2.46(dd, 1H), 2.34(m, 1H), 2.18(s, 3H), 2.04-1.93(m,2H), 1.89-1.77(m, 2H).

Aniline Intermediate 2

1-[(2-aminophenyl)oxy]-3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-propanoldihydrochloride

Prepared according to the method described in Aniline Intermediate 1.

APCI-MS m/z: 363, 365 [MH⁺]

The intermediate anilines 1 and 2 described above were used in thefollowing examples.

EXAMPLE 2 Thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

To a solution of 80 uL 0.2M 2-thiophenecarboxylic acid in N were IBTU(80uL, 0.2M/NMP) ,HoBT (80 uL, 0.2M/NMP), DIEA (30 uL, 0.5M/NMP) andpyridine (30 uL, 0.5M/NMP) added and stirred for 30 minutes before1-[(2-aminophenyl)oxy]-3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-propanol (75 uL, 0.2 M/NMP) wasadded. The mixture was stirred overnight at room temperature before itwas concentrated under reduced pressure to dryness. The product wasdiluted with 1000 uL dichloromethane and washed with with sat. NaHCO₃/aq(800 uL), 1.8% HCl/aq(800 uL) and sat NaC])aq.

The organic layer was concentrated under reduced pressure to dryness andused without further purification Yield 3.6 mg, 51%

APCI-MS m/z: 473.2 [MH⁺]¹H NMR (400 MHz, CD₃OD): δ 7.88-7.85 (d, 1H),7.74-7.65 (m, 2H), 7.34-7.28 (m, 2H), 7.27-7.21 (m, 1H), 7.20-7.15 (m,1H), 7.14-7.09 (dd, 1H), 7.06-7.00 (m, 1H), 6.96-6.91 (m, 2H), 5.18-5.12(m, 1H), 4.39-4.30 (m, 1H), 4.19-3.24 (m, 9H), 2.66-2.11 (m, 3H)

The following Examples 3 to 53 were prepared by methods analogous to themethod descnbed in Example 2.

EXAMPLE 3N-[(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-methyl]-benzamide

APCI-MS m/z: 524.3 [MH⁺]

EXAMPLE 4 Pyrazine-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}phenyl)-amide

APCI-MS m/z: 469.2 [MH⁺]

EXAMPLE 5 Cyclohexanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 473.3 [MH⁺]

EXAMPLE 6N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-phthalamicacid methyl ester

APCI-MS m/z: 525.2 [MH⁺]

EXAMPLE 7N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide

APCI-MS m/z: 449.2 [MH⁺]

EXAMPLE 8N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-ureido-acetamide

APCI-MS m/z: 463.2 [MH⁺]

EXAMPLE 94-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-butyramide

APCI-MS m/z: 490.3 [MH⁺]

EXAMPLE 10 1-Acetyl-piperidine-4-carboxylic acid(2-{3-[3-(4chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 516.3 [MH⁺]

EXAMPLE 11N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methoxy-benzamide

APCI-MS m/z: 497.2 [MH⁺]

EXAMPLE 122-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide

APCI-MS m/z: 504.3 [MH⁺]

EXAMPLE 132-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide

APCI-MS m/z: 506.2 [MH⁺]

EXAMPLE 14 Adamantane-1-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 525.3 [MH⁺]

EXAMPLE 152-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-phenyl-propionamide

APCI-MS m/z: 552.3 [MH⁺]

EXAMPLE 16N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-benzamide

APCI-MS m/z: 497.2

EXAMPLE 17 5-Methyl-thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 487.2 [MH⁺]

EXAMPLE 18 1-Acetyl-pyrrolidine-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 502.3 [MH⁺]

EXAMPLE 19 1,5-Dimethyl-1H-pyrazole-3-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolIdin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 485.3 [MH⁺]

EXAMPLE 20 5-Oxo-pyrrolidine-2-carboxylic acid(2-{3-[3-(4-chlorophenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 474.2 [MH⁺]

EXAMPLE 21 1H-Indole-6-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 506.2 [MH⁺]

EXAMPLE 22 Cyclobutanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 445.3 [MH⁺]

EXAMPLE 23N-(2-{3-[3-(4Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide

APCI-MS m/z: 419.2 [MH⁺]

EXAMPLE 24 Pentanoic acid(2-{3-[3-(4chloro-phenoxy)-pyrrolldin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 447.3 [MH⁺]

EXAMPLE 25 Pent-4-enoic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolIdin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 445.3 [MH⁺]

EXAMPLE 26 Cyclopentanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 459.3 [MH⁺]

EXAMPLE 27 Cyclopropanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 431.2 [MH⁺]

EXAMPLE 28N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isobutyramide

APCI-MS m/z: 433.3 [MH⁺]

EXAMPLE 29N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methylsulfanyl-acetamide

APCI-MS m/z: 451.2 [MH⁺]

EXAMPLE 302-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide

APCI-MS m/z: 476.2 [MH⁺]

EXAMPLE 31N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroy-propoxy}phenyl)-butyramide

APCI-MS m/z: 433.3 [MH⁺]

EXAMPLE 32N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide

APCI-MS m/z: 447.3 [MH⁺]

EXAMPLE 33N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-acetamide

APCI-MS m/z: 435.2 [MH⁺]

EXAMPLE 34N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2,2-dimethyl-propionamide

APCI-MS m/z: 447.2 [MH⁺]

EXAMPLE 35 5-Oxo-hexanoic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 475.3 [MH⁺]

EXAMPLE 36 Hexanoic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 461.3 [MH⁺]

EXAMPLE 372-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide

APCI-MS m/z: 501.2, 503.2 [MH⁺]

EXAMPLE 383-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide

APCI-MS m/z: 501.2, 503.2 [MH⁺]

EXAMPLE 39(4R)-N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-1,3-thiazolidine-4-carboxamideditrifluoroacetate

APCI-MS m/z: 478.2 [MH⁺]

EXAMPLE 40 Thiophene-2-carboxylic acid(2-{3-[4-(3,4dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 521.0, 523.0 [MH⁺]

EXAMPLE 41N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperdin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide

APCI-MS m/z: 515.2, 517.2[MH⁺]

EXAMPLE 42N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperdin-1-yl]-2-hydroxy-propoxy}-phenyl)-nicotinamide

APCI-MS m/z: 516.2, 518.2 [MH⁺]

EXAMPLE 43 Pyridine-2-carboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 516.2, 518.2 [MH⁺]

EXAMPLE 44N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isonicotinamide

APCI-MS m/z: 516.2, 518.2 [MH⁺]

EXAMPLE 45 Cyclohexanecarboxylic acid(2-{3-[4-(3,4-chloro-phenoxy)-piperldin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 521.3, 523.3 [MH⁺]

EXAMPLE 46N-(2-{3-[4-(3,4-Dichlorophenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}phenyl)-3-hydroxy-butyramide

APCI-MS m/z: 497.2, 499.3 [MH⁺]

EXAMPLE 47 5-Methyl-thiophene-2-carboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperdin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 535.2, 537.2 [MH⁺]

EXAMPLE 48 Cyclobutanecarboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 493.3, 495.2 [MH⁺]

EXAMPLE 49N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide

APCI-MS m/z: 467.2, 469.2 [MH⁺]

EXAMPLE 50 Pentanoic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 495.3,497.3 [MH⁺]

EXAMPLE 51 Pent-4-enoic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 493.3 ,495.2[MH⁺]

EXAMPLE 52 Cyclopentanecarboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide

APCI-MS m/z: 507.3, 509.3 [MH⁺]

EXAMPLE 53N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide

APCI-MS m/z: 495.3,497.3 [MH⁺]

EXAMPLE 54N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-2,2,2-trifluoroacetamidehydrochloride

A mixture of1-(2-aminophenoxy)-3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-propanol (10mg, 0.022 mmol), dichloromethane (3 ml) and Triethyl amine was cooled inan ice bath A solution of Trifluoro acetic anhydride (3.5 μl, 0.025mmol) in dichloromethane (2 ml) was then added and the mixture stirredat 0° C. until reaction completion. The mixture was diluted withdichloromethane, washed with 1M H₂SO₄, water, dried over natriumsulphate and concentrated to give an oil. The oil was treated with 1.0Methereal HCl solution to give the product as solid (9 mg).

APCI-MS: m/z 459,460 [MH⁺]

EXAMPLE 554-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-3-methyl-butyricacid

1-(2-aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-propanol(75 uL, 0.2M/NMP) was mixed with 3-methyl glutaric anhydride (3 eq, 225uL 0.2 M/NMP) to get a product containing both esther and amide. Afterevaporation of the mixture it was treated with 3 eq 0.5M LiOH in(TF/water 1:4) for two hours at 80° C. to hydrolyse the esther. Thereaction mixture was diluted with more water (2 mL) and the desiredproduct was extracted with 5×500 uL EtOAc which was evaporated todryness.

APCI-MS m/z: 539.2, 541.2 [MH⁺]

EXAMPLE 56N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-succinamicacid

Prepared according to the method described in Example 55.

APCI-MS m/z: 511.2, 513.2 [MH⁺]

Aniline Intermediate 3

1-(2-amino-5-methylphenoxy)-3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-propanol

APCI-MS m/z: 377.2, 379.1 [MH⁺]

¹H NMR (400 MHz, CDCl3): δ 7.26-7.21 (m, 2H), 6.79-6.74 (m, 2H),6.67-6.62 (m, 3H), 4.83-4.76 (m, 1H), 4.15-4.06 (m, 1H), 4.04-4.00 (d,2H), 3.73-3.64 (s, 2H), 3.47-3.35 (s, 1H), 3.14-2.56 (m, 6H),2.36-2.22(m, 4H), 2.05-1.95(m, 1H)

Aniline Intermediate 4

1-(2-amino-5-methylphenoxy)-3-[3-(4-fluorophenoxy)-1-pyrrolidinyl]-2-propanol

APCI-MS m/z: 361.1 [MH⁺]

¹H NMR (400 MHz, CDCl3): δ 7.00-6.94 (m, 2H), 6.81-6.76 (m, 2H),6.67-6.62(m, 3H), 4.81-4.74 (m, 1H), 4.15-4.06 (m, 1H), 4.03-3.99 (m,2H), 3.88-3.36 (m, 3H), 3.12-2.56 (m, 6H), 2.33-2.23(m, 4H),2.05-1.96(m, 1H)

The compounds of Examples 57 to 85 were prepared using one of theAniline Intermediates 3 and 4.

EXAMPLE 57 Furan-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 471.5, 473.5 [MH⁺]

EXAMPLE 58 1H-Pyrrole-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 470.5, 472.5 [MH⁺]

EXAMPLE 59 Thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 487.5, 489.5 [MH⁺]

EXAMPLE 60 Cyclopentanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrilidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 473.6, 475.5 [MH⁺]

EXAMPLE 61 5-Methyl-thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolldin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 501.5, 503.5 [MH⁺]

EXAMPLE 62 3-Chloro-thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 521.5, 532.5 [MH⁺]

EXAMPLE 63 5-Methyl-isoxazole-4-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 486.5, 488.6 [MH⁺]

EXAMPLE 64 [1,2,3]Thiadiazole-4-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrroldin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 489.5, 491.5[MH⁺]

EXAMPLE 65 3-Methyl-furan-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 485.5, 487.6 [MH⁺]

EXAMPLE 66 Cyclopent-1-enecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 471.6, 473.6 [MH⁺]

EXAMPLE 67 2-Methyl-furan-3-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrroldin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 485.6, 487.6 [MH⁺]

EXAMPLE 68 3-Methyl-thiophene-2-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 501.6, 503.5 [MH⁺]

EXAMPLE 69 5-Nitro-1H-pyrazole-3-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 516.5, 518.5 [MH+]

EXAMPLE 70 Thiophene-3-carboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 487.5, 489.5 [MH+]

EXAMPLE 71 Cyclobutanecarboxylic acid(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 459.5, 461.5 [MH+]

EXAMPLE 72 Furan-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 455.5 [MH+]

EXAMPLE 73 1H-Pyrrole-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 454.6 [MH+]

EXAMPLE 74 Thiophene-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 471.5 [MH⁺]

EXAMPLE 75 3-Chloro-thiophene-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 505.5, 507.5 [MH+]

EXAMPLE 76 5-Methyl-isoxazole-4-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenylamide

APCI-MS m/z: 470.5 [MH+]

EXAMPLE 77 3-Methyl-furan-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 469.6 [MH+]

EXAMPLE 78 Cyclopent-1-enecarboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 455.6 [MH+]

EXAMPLE 79 2-Methyl-furan-3-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 469.6 [MH+]

EXAMPLE 80 3-Methyl-thiophene-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 485.5 [MH+]

EXAMPLE 81 5-Chloro-thiophene-2-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 505.5, 507.5 [MH+]

EXAMPLE 82 Thiophene-3-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 471.5 [MH+]

EXAMPLE 83 2,5-Dimethyl-furan-3-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 483.6 [MH+]

EXAMPLE 84 Cyclobutanecarboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 443.6 [MH+]

EXAMPLE 85 Furan-3-carboxylic acid(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide

APCI-MS m/z: 455.5 [M+H⁺]

EXAMPLE 86N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-1H-pyrrole-2-carboxamlde

APCI-MS: m/z 454.1 [M+H⁺]

EXAMPLE 87N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-3-thiophenecarboxamide

APCI-MS: m/z 471.1 [M+H⁺]

EXAMPLE 88N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxy]phenyl}-2-thiophenecarboxamide,compound with trifluoroacetic acid

Aniline intermediate 3 (60 mg, 0.159 mmol), 2-thiophenecarboxylic acid(20.4 mg, 0.159 mmol) and HATU (72 mg, 0.191 mmol) were stirred indichloromethane (2 ml).

Diisopropylethylamine was added to pH 8. The mixture was stirredovernight and then concentrated. The residue was purified on silica(dichloromethane/methanol 98/2) followed by purificaton on C18 (2 gIsolute, acetonitfile/water 20/80 to 35/65 with 0.5% trifluoroaceticacid) to give the title compound (75 mg, 79%).

¹H-NMR (400 MHz, MeOD): δ 7.86 (m, 1H), 7.72 (m, 1H), 7.50 (m, 1H), 7.29(m, 3H), 7.16 (m, 2H), 7.07 (m, 1H), 6.91 (m, 2H), 5.10 (m, 1H),3.82-4.17 (m, 4H), 3.24-3.69 (m, 4H), 2.13-2.64 (m, 2H), 1.38 (m, 3H).MS-APCI+: m/z 487 [MH⁺]

EXAMPLE 89N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-2-thiophenecarboxamiide

APCI MS APCI-MS: m/z 471.1 [M+H⁺]

EXAMPLE 90N-{2-[(3-{3-[(4-chlorophenyl)oxyl-1-pyrroldinyl}-2-hydroxpropyl)oxy]phenyl}-2-furancarboxamide

APCI-MS: m/z 456.9 [M+H⁺]

EXAMPLE 91N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]phenyl}-1-pyrrole-2-carboxamide

APCI-MS: m/z 456.1 [M+H⁺]

EXAMPLE 92N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-1H-pyrrole-3-carboxamide

APCI-MS: m/z 470.0 [M+H⁺]

EXAMPLE 93N-{2-[(3-{3-[(4-fluorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-methylphenyl}-2-furancarboxamide

APCI-MS: m/z 4551 M+H⁺]

EXAMPLE 94N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxy]phenyl}cyclopentanecarboxamide,compound with trinfluoracetic acid

The compound (80 mg, 86%) was prepared from aniline intermediate 3 (60mg, 0.159 mmol) and cyclopentanecarboxylic acid (18 μl, 0.159 mmol) asdescnbed in Example 88.

¹H-NMR (400 MHz, MeOD): δ 7.59 (m, 1H), 7.29 (m, 2H), 7.19 (m, 1H), 7.09(m, 1H), 6.97 (m, 3H), 5.17 (m, 1H), 3.86-4.23 (m, 4H), 3.35-3.73 (m,4H), 2.86 (m, 1H), 1.45 (bs, 3H).

MS-APCI+: m/z 473 [MH⁺]

EXAMPLE 95N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide

The compound was prepared using an analogous method as in Example 88.

APCI-MS: m/z 465 [MH⁺]

EXAMPLE 96N-(2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide

The compound was prepared using an analogous method as in Example 88.

APCI-MS: m/z 472 [MH⁺]

EXAMPLE 97N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide

The compound was prepared using an analogous method as in Example 88.

APCI-MS: m/z 529 [MH⁺]

EXAMPLE 98N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide

The compound was prepared using an analogous method as in Example 88.

APCI-MS: m/z 481 [MH⁺]

EXAMPLE 99N-(2-{3-[4-(3,4-Dichloro-phenylamino)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide

The compound was prepared using an analogous method as in Example 88.

APCI-MS: m/z 528 [MH⁺]

THP-1 Chemotaxis Assay

Introduction

The assay measured the chemotactic response elicited by MIP-1α chemokinein the human monocytic cell line TBP-1. The compounds of the Exampleswere evaluated by their ability to depress the chemotactic response to astandard concentration of MP-lx chemokine.

Methods

Culture of THP-1 cells

Cells were thawed rapidly at 37° C. from frozen aliquots and resuspendedin a 25 cm flask containing 5 ml of RPI-1640 medium supplemented withGlutamax and 10% heat inactivated fetal calf serum without antibiotics(RPMI+10%HIFCS). At day 3 the medium is discarded and replaced withfresh medium

THP-1 cells are routinely cultured in RPMI-1640 medium supplemented with10% heat inactivated fetal calf serum and glutamax but withoutantibiotics. Optimal growth of the cells requires that they are passagedevery 3 days and that the minimum subculture density is 4×10+5 cells/ml.

Chemotaxis Assay

Cells were removed from the flask and washed by centrigation inRPMI+10%HEFCS+glutamax. The cells were then resuspended at 2×10+7cells/mi in fresh medium (RPMI+10%HIFCS+glutamax) to which was addedcalcein-AM (5 μl of stock solution to 1 ml to give a final concentrationof 5×10⁻⁶ M). After gentle mixing the cells were incubated at 37° C. ina CO₂ incubator for 30 minutes. The cells were th diluted to 50 ml withmedium and washed twice by centrifigation at 400 ×g. Labelled cells werethen resuspended at a cell concentration of 1×10+7 cells/ml andincubated with an equal volume of MIP-1α antagonist (10⁻¹⁰M to 10⁻⁶Mfinal concentration) for 30 minutes at 37° C. in a humidified CO₂incubator.

Chemotaxis was performed using Neuroprobe 96-well chemotaxis platesemploying 8 μM (filters (cat no. 101-8). Thirty microlitres ofchemoattractant supplemented withy various concentrations of antagonistsor vehicle were added to the lower wells of the plate in triplicate. Thefilter was then carefully positioned on top and then 25 μl of cellspreincubated with the corresponding concentration of antagonist orvehicle were added to the surface of the filter. The plate was thenincubated for 2 hours at 37° C. in a humidified CO₂ incubator. The cellsremaining on the surface were then removed by adsorption and the wholeplate was centrifuged at 2000 rpm for 10 minutes. The filter was thenremoved and the cells that had migrated to the lower wells werequantified by the fluorescence of cell associated calcein-AM. Cellmigration was then expressed in fluorescence units after subtraction ofthe reagent blank and values were standardized to % migration bycomparing the fluorescence values with that of a known number oflabelled cells. The effect of antagonists was calculated as % inhibitionwhen the number of migrated cells were compared with vehicle.

1. A compound of general formula

wherein: m is 0, 1, 2 or 3; each R¹ independently represents halogen,cyano, nitro, carboxyl, hydroxyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NR⁹R¹⁰, C₃-C₆cycloalkylamino, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl, C₁-C₆alkylcarbonylamino, sulphonamido, C₁-C₆ alkylsulphonyl, —C(O)NR¹¹R¹²,—NR¹³C(O)—(NH)_(P)R¹⁴, phenyl, or C₁-C₆ alkyl optionally substituted bycarboxyl or C₁-C₆ alkoxycarbonyl; p is 0 or 1; X represents an oxygenatom or a CH₂, OCH₂, CH₂O, CH₂NH, NH, carbonyl or sulphonyl group and Yrepresents a nitrogen atom or a CH or C(OH) group, provided that when Xrepresents an oxygen atom or a CH₂O, CH₂NH or NH group, then Yrepresents a CH group; Z¹ represents a group (CH₂)_(q) where q is 1 or2; Z² represents a bond or a group CH₂, with the proviso that when Z¹ isCH₂, Z² is CH₂, and when Z¹ is (CH₂)₂. Z² is a bond; Q represents anoxygen or sulphur atom or a group CH₂ or NH; R represents a group

n is 0, 1 or 2; each R³ independently represents a C₁-C₆ alkyl, C₁-C₆alkoxycarbonyl, —CH₂OH or carboxyl group; R⁴, R⁵, R⁶ and R⁷ eachindependently represent a hydrogen atom or a C₁-C₆ alkyl group, or R⁴,R⁵, R⁶ and R⁷ together represent a C₁-C₄ alkylene chain linking the twocarbon atoms to which they are attached to form a 4- to 7-memberedsaturated carbocycle, or R⁵, R⁶ and R⁷ each represent a hydrogen atomand R⁴ and R⁸ together with the carbon atoms to which they are attachedform a 5- to 6-membered saturated carbocycle; R⁸ represents a hydrogenatom, a C₁-C₆ alkyl group or is linked to R⁴ as defined above; R⁹ andR¹⁰ each independently represent a hydrogen atom or a C₁-C₆ alkyl group,or R⁹ and R¹⁰ together with the nitrogen atom to which they are attachedform a 4- to 7-membered saturated heterocycle; R¹¹ and R¹² eachindependently represent a hydrogen atom or a C₁-C₆ alkyl groupoptionally substituted by C₁-C₆ alkoxycarbonyl; R¹³ represents ahydrogen atom or a C₁-C₆ alkyl group; R¹⁴ represents a hydrogen atom, ora C₁-C₆ alkyl group optionally substituted by carboxyl, C₁-C₆ alkoxy orC₁-C₆ alkoxycarbonyl; R¹⁵ represents a group C₂-C₆ alkyl, C₂-C₆ alkenyl,C₃-C₆ cycloalkyl, C₅-C₆ cycloalkenyl, adamantyl, phenyl or a saturatedor unsaturated 5- to 10-membered heterocyclic ring system comprising atleast one heteroatom selected from nitrogen, oxygen and sulphur, whereineach group may be optionally substituted by one or more substituentsindependently selected from nitro, hydroxyl, oxo, halogen, carboxyl,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl, C₁-C₆alkoxycarbonyl, phenyl and —NHC(O)—R¹⁷, with the proviso that R¹⁵ doesnot represent an unsubstituted 1-pyrrolidinyl, an unsubstituted1-piperidinyl or an unsubstituted 1-hexamethyleneiminyl group; t is 0,1, 2 or 3; each R¹⁶ independently represents halogen, cyano, nitro,carboxyl, hydroxyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NR¹⁸R¹⁹, C₃-C₆cycloalkylamino, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl, C₁-C₆alkylcarbonylamino, sulphonamido (—SO₂NH₂), C₁-C₆ alkylsulphonyl,—C(O)NR²⁰R²¹, —NR²²C(O)(NH)_(v)R²³, phenyl, or C₁-C₆ alkyl optionallysubstituted by carboxyl or C₁-C₆ alkoxycarbonyl; R¹⁷ represents a C₁-C₆alkyl, amino or phenyl group; R¹⁸ and R¹⁹ each independently represent ahydrogen atom or a C₁-C₆ alkyl group, or R¹⁸ and R¹⁹ together with thenitrogen atom to which they are attached form a 4- to 7-memberedsaturated heterocycle; R²⁰ and R²¹ each independently represent ahydrogen atom or a C₁-C₆ alkyl group optionally substituted by C₁-C₆alkoxycarbonyl; v is 0 or 1; R²² represents a hydrogen atom or a C₁-C₆alkyl group; and R²³ represents a hydrogen atom, or a C₁-C₆ alkyl groupoptionally substituted by carboxyl, C₁-C₆ alkoxy or C₁-C₆alkoxycarbonyl; or a pharmaceutically acceptable salt or solvatethereof.
 2. A compound according to claim 1, wherein X represents anoxygen atom or a CH₂ or NH group.
 3. A compound according to claim 1,wherein Y represents a CH group.
 4. A compound according to claim 1,wherein Q represents an oxygen atom.
 5. A compound according to claim 1,wherein R¹⁵ represents a group C₂-C₅ alkyl, C₂-C₄ alkenyl, C₃-C₆cycloalkyl, C₅-C₆ cycloalkenyl, adamantyl, phenyl or a saturated orunsaturated 5- to 10-membered heterocyclic ring system comprising atleast one heteroatom selected from nitrogen, oxygen and sulphur, whereineach group may be optionally substituted by one, two or threesubstituents independently selected from hydroxyl, oxo, halogen,carboxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₆alkylcarbonyl, Cl-C₆ alkoxycarbonyl, phenyl and —NHC(O)—R¹⁷.
 6. Acompound according to claim 5, wherein the saturated or unsaturated 5-to 10-membered heterocyclic ring system comprising at least oneheteroatom selected from nitrogen, oxygen and sulphur, is pyrrolidinyl,piperidinyl, pyrazolyl, thiazolidinyl, thienyl, thiadiazolyl,isoxazolyl, pyrrolyl, furanyl, thiazolyl, indolyl, quinolinyl,benzimidazolyl, triazolyl, tetrazolyl or pyridinyl.
 7. A compoundaccording to claim 1, wherein each R¹⁶ independently represents halogen,cyano, C₁-C₄ alkoxy, C₁-C₄ alkoxycarbonyl, C₁-C₄haloalkyl, C₁-C₄alkylcarbonyl, phenyl or C₁-C₄ alkyl.
 8. A compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as defined in claim1 being selected from: Thiophene-2-carboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-nicotinamide,Pyridine-2-carboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isonicotinamide,Cyclohexanecarboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,5-Methyl-thiophene-2-carboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,Cyclobutanecarboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,Pentanoic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,Pent-4-enoic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,Cyclopentanecarboxylic acid(2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide,N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,4-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-3-methyl-butyricacid,N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-succinamicacid,N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,N-(2-{3-[4-(3,4-Dichloro-phenylamino)-piperidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide.9. A process for the preparation of a compound of formula (I) as definedin claim 1 which comprises reacting a compound of general formula

or a salt thereof, wherein m, n, t, R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁶, Q,Z¹ and Z² are as defined in formula (I), with a compound of generalformulaR¹⁵—CO₂H  (III) or chemically equivalent derivative thereof, wherein R¹⁵is as defined in formula (I); and optionally thereafter forming apharmaceutically acceptable salt or solvate of the compound of formula(I) obtained.
 10. A pharmaceutical composition comprising a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,as claimed in any one of claim 1 in association with a pharmaceuticallyacceptable adjuvant, diluent or carrier.
 11. A process for thepreparation of a pharmaceutical composition as claimed in claim 10 whichcomprises mixing a compound of formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, as claimed in claim 1 with apharmaceutically acceptable adjuvant, diluent or carrier. 12-18.(canceled)
 19. A method of treating an inflammatory disease in a patientsuffering from, or at risk of, said disease, which comprisesadministering to the patient a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as claimed in claim
 1. 20. A method of treating anairways disease in a patient suffering from, or at risk of, saiddisease, which comprises administering to the patient a therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, as claimed in claim
 1. 21. A methodof treating a human disease or condition in which modulation ofchemokine receptor activity is beneficial, in a patient suffering from,or at risk of, said disease or condition, which comprises administeringto the patient a therapeutically effective amount of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,as claimed in claim
 1. 22. A method of treating rheumatoid arthritis ina patient suffering from, or at risk of, rheumatoid arthritis, whichcomprises administering to the patient a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as claimed in claim
 1. 23. A method of treatingchronic obstructive pulmonary disease in a patient suffering from, or atrisk of, said disease, which comprises administering to the patient atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as claimed inclaim
 1. 24. A method of treating asthma, in a patient suffering from,or at risk of, asthma, which comprises administering to the patient atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as claimed inclaim
 1. 25. A method of treating multiple sclerosis in a patientsuffering from, or at risk of, multiple sclerosis, which comprisesadministering to the patient a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as claimed in claim 1.